Why do neurons in the mature central nervous system (CNS) die after injury? White matter ischemia (stroke) leads to axon injury and then in most cases to death of CNS neurons. Thus, for example, ischemic optic neuropathy leads to retinal ganglion cell (RGC, a type of CNS neuron) dysfunction and death, and permanent loss of vision. Although many of the downstream molecular pathways of cell death and apoptosis are under intensive study, the upstream signals that regulate survival and axon regeneration after axon injury are not known. Recent evidence suggests that RGCs die after axon injury for two reasons: they are cut off from target-derived trophic signals, and they become less responsive to such signals. Trophic responsiveness, survival and regeneration can be enhanced by elevating cyclic AMP (cAMP), but the signal transduction pathways remain largely unstudied. Here we will use the rodent retina and optic nerve as a model system for CNS neurons and their axonal, white matter pathways, respectively, and test the hypothesis that compartmentalized signaling on a family of scaffold proteins called AKAPs regulate survival and regeneration signaling in a novel model of white matter stroke in the optic nerve. In three Specific Aims, we will (1) identify the specific adenylyl cyclases responsible for cAMP signaling in primary neurons~ (2) identify the specific AKAP-related signaling pathways potentiated by cAMP and contributing to neuronal survival and regeneration~ and (3) determine whether manipulating AKAP-mediated signalosomes in vivo regulates neuronal survival and regeneration in vivo after ischemic axon injury. We hope through these experiments to determine the molecular basis for the failure of RGC survival after ischemic axon injury, and ultimately to develop new treatments to maintain CNS neuronal survival after white matter ischemia. PUBLIC HEALTH RELEVANCE: Stroke leads to injury and then in most cases to death of central nervous system neurons. Similarly, ischemic optic neuropathy leads to retinal ganglion cell (RGC, a type of CNS neuron) axon injury, followed by RGC dysfunction and death, and permanent loss of vision. Here we will study the signaling of neuronal survival and regeneration in a new model of white matter ischemic axon injury, using the optic nerve as a relevant model. Our hope is to understand why RGCs fail to survive after ischemic optic neuropathy, and to develop new treatments to maintain CNS neuronal survival after white matter ischemia.